tbuckley/cabot-search huggingface dataset:
Abstract 1087: Development and characterization of a bispecific antibody (GB265) against PD-L1 and TIGIT
Authors: Su Huang, Riyao Yang, Cai Huang, Saroja Putrevu, Nathan S. Fay, Kimberly Wright, Mohd Saif Zaman, Betty Huang, Bo Wang, Meredith Wright, Yanan Wang, Xuefei Tian, Yue Liu
Journal: Cancer Research (2022)

Abstract Background: Cancer immunotherapy has transformed cancer therapy. In particular, blockade of the PD-L1/PD-1 axis with PD-1 or PD-L1 antibodies has achieved successful and durable treatment outcomes in some patients across a variety of cancer types. However, primary or acquired resistance to immunotherapy and adverse effects have been observed in cancer patients, due to a hostile TME and the immunosuppressive activity of various inhibitory checkpoint receptors and their ligands on immune cells and cancer cells. It was recently reported that dual blockade of PD-1/PD-L1 and TIGIT/CD155 could improve treatment efficacy in NSCLC patients. We therefore develop bispecific antibody against both PD-L1 and TIGIT with the aim of enhancing the efficacy of therapy and mitigating potential adverse effects. Methods: We obtained TIGIT binders by VHH library panning, and constructed PD-L1/TIGIT BsAbs of two different structures either by fusing the TIGIT VHH to a PD-L1 IgG or by fusing the TIGIT VHH to a PD-L1 VHH-Fc. TIGIT binding and CD155 blocking was analyzed by fluorescence-activated cell sorting (FACS) using Jurkat cells stably expressing TIGIT. Function assays were conducted with a co-culture system of H1975 stably expressing OKT3 and induced human exhausted T cells or luciferase reporter Jurkat cells with high expression of PD-1 and TIGIT. Results: Both bispecific antibodies effectively bind TIGIT on T cells and PD-L1 on PD-L1 positive cancer cells. Interaction between BsAb and the two targets bridge the T cell and the cancer cell and result in the clustering of the antibody-antigen complexes at the contact area of the two cells. Functionally, GB265 antibodies effectively blocked CD155 and PD-1 signal pathways in the cell-based reporter system and exhibited ADCC function specifically to target cancer cells. Conclusion: GB265 antibodies have the potential to outperform PD-L1 and TIGIT monospecific antibodies or their combinations in rejuvenating anti-tumor immunity in cancer patients due to its bridging activity and dual blockade function. Citation Format: Su Huang, Riyao Yang, Cai Huang, Saroja Putrevu, Nathan S. Fay, Kimberly Wright, Mohd Saif Zaman, Betty Huang, Bo Wang, Meredith Wright, Yanan Wang, Xuefei Tian, Yue Liu. Development and characterization of a bispecific antibody (GB265) against PD-L1 and TIGIT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1087.
Abstract 1813: DIACC2010, a selective inhibitor of KIF20A
Authors: Yves COLLETTE, Rémy CASTELLANO, Michel AURRAND-LIONS, Hélène SICARD, Norbert VEY, Cécile BOUGERET
Journal: Cancer Research (2022)

Abstract Mitotic kinesins are essential regulators of cancer cell replication and migration. The microtubule associated motor protein KIF20A (also called MKlp2), a member of the kinesin-6 family, plays an essential role during cytokinesis and is also involved in the fission of RAB6-positive vesicles from Golgi membrane, therefore contributing to intracellular vesicular trafficking (1). KIF20A plays a critical role in the development and progression of many cancers, and its high expression is associated with disease progression and poor survival outcome (2). More specifically, immature hematopoietic cells, exhibit high KIF20A expression, whereas mature peripheral blood cells do not (3). Herein we describe the preclinical anti-leukemic efficacy of DIACC2010, sole-in-class selective KIF20A inhibitor. DIACC2010 demonstrated potent and consistent cytotoxic activity in-vitro against a panel of 9 human AML cell lines, with median IC50 of 40 nM (range 10-77 nM). In the same experimental conditions, cytarabine (CYTA) had median IC50 of 207 nM (range 4-1580 nM). In parallel, no in-vitro toxicity of DIACC2010 was observed on human normal cells such as peripheral blood mononuclear cells (PBMC) and primary hepatocytes (IC50 &amp;gt;50 µM). DIACC2010 was subsequently evaluated in-vivo in xenograft models of CYTA-sensitive and CYTA-resistant AML cell lines: DIACC2010 significantly improved overall survival as compared to CYTA in all models, with dose-dependent efficacy. On a mechanistic standpoint, DIACC2010-exposed AML cells displayed characteristic Golgi scattering leading to cell death, as hallmarks of DIACC2010 mode of action and target engagement. Altogether, these results confirm the relevance of KIF20A-directed therapeutic approaches and support the development of DIACC2010 for the treatment of AML. (1) Coupling fission and exit of RAB6 vesicles at Golgi hotspots though kinesin-myosin interactions, S. Miserey-Lenkei et al, Nature com, 2017, 104:300 (2) Prognostic significance of KIF2A and KIF20A expression in human cancer. X. Li et al, Medicine, 2019, 98:46 (3) KIF20A, highly expressed in immature hematopoietic cells, supports the growth of HL60 cell line, H. Morita et al, Int J Immunol, 2018,108:607 Citation Format: Yves COLLETTE, Rémy CASTELLANO, Michel AURRAND-LIONS, Hélène SICARD, Norbert VEY, Cécile BOUGERET. DIACC2010, a selective inhibitor of KIF20A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1813.
Abstract 2270: Hyperlipidemia promotes aggressive variant prostate cancer via RNA-binding protein Quaking
Authors: Hyun Ho Han, Jin Sol Sung, Dong Wook Song, Cheol Keun Park, Nam Hoon Cho, Young Deuk Choi, Woo Jin Ko
Journal: Cancer Research (2022)

Abstract Introduction: Hyperlipidemia has been associated with increased risk of advanced stage and high Gleason grade prostate cancer (PCa), yet the underlying mechanism is not completely understood. Quaking (QKI) is an RNA-binding protein (RBP) that regulate lipid metabolism. For PCa, QKI overexpression has been associated with increased chance of metastatic recurrence. Method: We performed RNA sequencing of prostate cancer tissues of hyperlipidemia (n = 12) and normolipidemia (n=32). Tissue samples were acquired by MRI-US fusion targeted biopsy. DESeq2 and GSEA was used to identify differently expressed genes and enriched genesets. A web-based RBP motif screening tool TRANSITE was utilized to identify active RBPs in hyperlipidemia-associated PCa. Results: PCa samples of hyperlipidemia patients exhibited poorer histology than normolipidemia PCA. RNA sequencing found that hyperlipidemia-associated PCa is enriched of Myc-regulated genes as well as interferon or innate immunity-associated genes. Interestingly, hyperlipidemia-associated PCa gene expression signature identified PCa samples devoid of common PCa genetic alterations - TMPRSS2-ERG fusion and PTEN deletion/mutation. RBP motif screening found QKI as one of the top enriched RBP in hyperlipidemia-associated PCa transcriptome. In a separate a consecutive radical prostatectomy series (n=190), we found that QKI-high (immunohistochemistry staining score 2-3) tumors had significantly higher serum cholesterol than QKI-low (score 0-1) tumors. Overexpression and knockdown experiments proved that QKI is responsible of rapid cell proliferation and interferon-related inflammatory gene expressions, In silico analysis predicted QKI overexpressing cancer cells are susceptive to stain-mediated ferroptosis-like cell death. Mechanistically, QKI regulates expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which dictates the sensitivity of QKI overexpressing cells to ferroptosis. Conclusion: Hyperlipidemia was associated with aggressive pathologic characteristics of PCa without TMPRSS2-ERG fusion or PTEN deletion/mutation, and high tissue expression of QKI, an RNA-binding protein. QKI overexpression in PCa increased sensitivity to ACSL4-mediated ferroptosis by statins. This explains the epidemiological associations between hyperlipidemia and PCa, and will guide molecular subtype-driven drug repurposing studies. Citation Format: Hyun Ho Han, Jin Sol Sung, Dong Wook Song, Cheol Keun Park, Nam Hoon Cho, Young Deuk Choi, Woo Jin Ko. Hyperlipidemia promotes aggressive variant prostate cancer via RNA-binding protein Quaking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2270.
Abstract 1041: HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations
Authors: Farbod Shojaei, Farbod Shojaei, Jill M. Ricono, Che Fang, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings
Journal: Cancer Research (2022)

Abstract SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is an attractive target in oncology drug development due to its dual roles on the direct growth and proliferation of cancer cells and also acting as an immune checkpoint molecule to suppress tumor immunity. HBI-2376 is an orally bioavailable selective SHP2 inhibitor that is being developed for the treatment of solid tumors harboring KRAS or EGFR mutations, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Additionally, HBI-2376 has the potential to suppress tumor growth via induction of the activity of immune infiltrating cells in the TME (tumor microenvironment). In a head-to-head comparison, in vitro studies showed greater potency of HBI-2376 to inhibit cell proliferation in a variety of cancer cell lines compared to other SHP2 inhibitors such as TNO-155 (Novartis AG) and RMC-4550 (Revolution Medicines). Consistently, HBI-2376 found to be more efficacious in tumor growth inhibition than TNO-155 and RMC-4550 in NCI-H1975L858R_T790M_C797S osimertinib-resistant cell line and other tumor models. In addition to xenograft models, we tested efficacy of HBI-2376 as single agent or in combination with anti-PD1 mAb in MC38 CRC syngeneic model. Consistent with xenograft data, HBI-2376 showed greater efficacy in tumor growth inhibition vs. TNO-155 and RMC-4550 both as single agent and in combination therapy. IHC data showed reduction in infiltration of M2 macrophages (F4/80+Arg1+) in the HBI-2376 treated tumors suggesting a MoA for its greater efficacy in MC38 model. Furthermore, Western blotting showed inhibition of p-ERK and DUSP6 in HBI-2376 treated cells indicative of a biomarker of response to the therapy. These findings, along with a positive safety profile led to HBI-2376 IND clearance by FDA and suggested promising responses in NSCLC or CRC patients in the forthcoming clinical studies. Citation Format: Farbod Shojaei, Farbod Shojaei, Jill M. Ricono, Che Fang, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings. HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1041.
Abstract CT546: A phase 2, multicenter study to evaluate the efficacy and safety of TACE sequential tislelizumab as adjuvant therapy in patients with HCC at high risk of recurrence after curative resection
Authors: Tingbo Liang, Zongli Zhang, Jinfang Zheng, Yijun Wang, Jialin Zhang, Bo Li, Tao Ma, Yunfei Xu, Changxiong Wu, Quan Sun, Yiman Meng, Xiaoli Yang
Journal: Cancer Research (2022)

Abstract Background: Surgical resection is one of the most important radical treatment in hepatocellular carcinoma (HCC). However, the 5-year recurrence rate of HCC after surgery is up to 70%, hampering further improvement in the prognosis of HCC patients. Risk factors for recurrence include microvascular invasion (MVI), multiple lesion and solitary tumor ≥ 5 cm, etc. Postoperative adjuvant treatment with transarterial chemoembolization (TACE) can reduce the recurrence rate and improve overall survival (OS) for patients with high risk of recurrence to some extent. TACE treatment promotes the release of tumor related antigen and the recruitment of immune cells by killing tumor cells, thereby promoting the anti-tumor immune response; it may have a potential synergistic effect with PD-1 blockade. Currently, there is no ongoing study on TACE combined with immunotherapy as postoperative adjuvant therapy for HCC. This is an open-label, multicenter, phase II study to evaluate the efficacy and safety of TACE sequential tislelizumab as adjuvant therapy in HCC patients with high risk of recurrence after curative resection (NCT04981665). Trial design: Eligible patients are ≥18 y, ECOG PS 0 or 1, Child-Pugh class A, diagnosed with HCC confirmed by histopathology or cytology, with no prior systematic treatment and locoregional therapy for HCC, and have received a curative resection with high risk of recurrence fulfilling one of the following criteria: (1) a solitary tumor &amp;gt; 5 cm, (2) solitary tumor &amp;gt; 2 cm and ≤ 5 cm with MVI, (3) 2-3 lesions. 50 pts will receive TACE treatment once (4±1 w) after curative resection, then followed by tislelizumab 200 mg IV Q3W (5±2 d). Tislelizumab will be administered until disease recurrence, intolerable toxicity, death, withdrawal of consent or completion of a maximum of 17 cycles of tislelizumab. Primary endpoint is 2-year recurrence-free survival rate (2-year RFS rate). Secondary endpoints include RFS, time to recurrence, OS, 1-year RFS rate, 1-year and 2-year OS rate, and safety. Exploratory endpoints include biomarkers related to the response and prognosis of adjuvant TACE sequential tislelizumab therapy. Citation Format: Tingbo Liang, Zongli Zhang, Jinfang Zheng, Yijun Wang, Jialin Zhang, Bo Li, Tao Ma, Yunfei Xu, Changxiong Wu, Quan Sun, Yiman Meng, Xiaoli Yang. A phase 2, multicenter study to evaluate the efficacy and safety of TACE sequential tislelizumab as adjuvant therapy in patients with HCC at high risk of recurrence after curative resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT546.
Abstract 1634: Reduction or loss of <i>Msh2</i> confers resistance to temozolomide in glioblastoma
Authors: Montserrat Puigdelloses Vallcorba, Alice Buonfiglioli, Gonzalo Piñero, Zhihong Chen, Dolores Hambardzumyan
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The only intervention that has improved the survival rate of GBM patients over the past several decades has been combining temozolomide (TMZ) with radiotherapy (RT), which increased median survival by only ~2.5 months to where it currently stands at ~15 months. Unfortunately, all GBM patients eventually die due to tumor recurrence. Intrinsic or acquired resistance to TMZ is a significant contributing factor to tumor progression, and various mechanisms have been suggested, including deficiencies in DNA mismatch repair (MMR) genes such as MSH2. Utilizing patient GBM samples from the TCGA, we have identified a correlation between low MSH2 expression and shorter patient survival. To test the biological significance of Msh2 in GBM growth and resistance to TMZ and immunotherapy, we have generated immunocompetent genetically engineered mouse models (GEMMs) of GBM with germline or somatic loss of Msh2. To generate tumors with reduced or abrogated Msh2, we utilized GEMMs based on the RCAS/tv-a gene transfer system in combination with mice that exhibited heterozygous and homozygous loss of Msh2. When PDGFB was overexpressed in combination with the silencing of Tp53 to induce tumors, tumor-bearing mice with reduced or deficient Msh2 demonstrated shorter survival time compared to wild-type tumor-bearing mice. In addition, our results indicate Msh2 deficiency increases the malignancy of gliomas. Our data demonstrate that two weeks of TMZ treatment at a clinically relevant dose of 25 mg/kg provides a significant survival advantage in WT-tumor-bearing mice, while no efficacy was observed in tumor-bearing mice with either heterozygous or homozygous loss of Msh2. We are currently evaluating the role of Msh2 in the efficacy of immune checkpoint inhibitors in glioblastoma. Citation Format: Montserrat Puigdelloses Vallcorba, Alice Buonfiglioli, Gonzalo Piñero, Zhihong Chen, Dolores Hambardzumyan. Reduction or loss of Msh2 confers resistance to temozolomide in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1634.
Association Between Changes in Perivascular Adipose Tissue Density and Plaque Progression
Authors: Sang-Eun Lee, Ji Min Sung, Daniele Andreini, Mouaz H. Al-Mallah, Matthew J. Budoff, Filippo Cademartiri, Kavitha Chinnaiyan, Jung Hyun Choi, Eun Ju Chun, Edoardo Conte, Ilan Gottlieb, Martin Hadamitzky, Yong Jin Kim, Byoung Kwon Lee, Jonathon A. Leipsic, Erica Maffei, Hugo Marques, Pedro de Araújo Gonçalves, Gianluca Pontone, Sanghoon Shin, Pieter H. Kitslaar, Johan H.C. Reiber, Peter H. Stone, Habib Samady, Renu Virmani, Jagat Narula, Daniel S. Berman, Leslee J. Shaw, Jeroen J. Bax, Fay Y. Lin, James K. Min, Hyuk-Jae Chang
Journal: JACC. Cardiovascular imaging (2022)
Abstract 5491: Targeting importin-YAP axis in pancreatic ductal adenocarcinoma
Authors: Renya Zeng, Jixin Dong
Journal: Cancer Research (2022)

Abstract Background: To date, pancreatic ductal adenocarcinoma (PDAC) remains to have a dismal prognosis, with a 5-year survival rate of only 10%, which brings out an imperative to develop new therapeutic strategies to improve patient outcome. Recently, aberrant nucleocytoplasmic transport machinery in cancer cells has emerged as a rational therapeutic target. We aim to validate the nuclear importin complex involved in the import of macromolecules across the nuclear membrane as a potential therapeutic target in PDAC. Methods: Tet-inducible shRNA and FDA-approved agent (Ivermectin) were used for the inhibition of importins. Cell death (apoptosis and pyroptosis) was detected by western blot. In vivo tumor growth of human and mouse PDAC cells was evaluated in immunocompetent and immunodeficient animal models. MTT assay was employed to evaluate the patient-derived organoid viability following drug treatment. Results: We found that PDAC cells/patients harbored unusually higher levels of importins. Inducible knockdown of importin-α2/α5 (KPNA2/KPNA1) or importin-β1 (KPNB1) strongly suppressed PDAC tumor growth and induced apoptosis and pyroptosis. Interestingly, the importin inhibitor Ivermectin (an FDA-approved antiparasitic agent) worked effectively in PDAC cells, patient-derived organoids and animal models. Mechanistically, we show that importins associate with YAP (the transcriptional coactivator of the Hippo pathway) and control its expression at mRNA levels. In line with these observations, the expression levels of importin-αs, importin-β1, and YAP are positively correlated in PDAC patients. Conclusion: Our study identifies the importin complex as a prognostic marker and therapeutic target for pancreatic cancer and is expected to provide preclinical evidence for the evaluation of Ivermectin in PDAC patients. Citation Format: Renya Zeng, Jixin Dong. Targeting importin-YAP axis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5491.
Abstract 1533: Long non-coding RNA control of cancer cell growth
Authors: Tong Su, Bobby Kong, Calvin Huang, Jonathan Zhu, Colleen McHugh
Journal: Cancer Research (2022)

Abstract Long non-coding RNAs (lncRNAs) are involved in controlling regulatory networks critical for gene expression, cellular growth, and development. Altered expression of lncRNAs are associated with tumor progression in multiple types of human cancers, but the mechanisms by which lncRNAs may control growth and proliferation in cancer cells remain unknown in most cases. Development of interventions targeting non-coding RNA regulation of cell growth would open new avenues for cancer treatment. To identify growth regulatory pathways controlled by non-coding RNAs, we used proteomics and genomics tools to study the effect of changes in lncRNA expression levels in human cancer cell lines. First, we identified five growth regulator lncRNAs based on data mining of CRISPR/Cas9 screens and high throughput sequencing studies from patient tumor and normal cells. These lncRNAs have been associated with progression and metastasis in breast, lung and colon cancers. We hypothesized that growth regulator lncRNAs play a role in cancer development by recruiting effector proteins to regulate gene expression. Next, we evaluated the cellular growth phenotype for each lncRNA in overexpression and knockdown strains using multiple established cancer cell lines. We analyzed cellular transcriptome changes after lncRNA perturbation using high-throughput RNA sequencing. Finally, RNA-protein interactions for each growth regulator lncRNA were identified using an RNA hybridization capture method paired with mass spectrometry that enables purification of direct and specific endogenous RNA-binding proteins. Using this combination of transcriptomics and proteomics data, we discovered that perturbation of growth regulator lncRNAs results in dysregulation of growth signaling pathways and increased expression of p53. We are currently identifying the sequence and structure determinants of RNA-protein complex formation to uncover the mechanisms of action of lncRNAs in controlling cancer cell growth. Citation Format: Tong Su, Bobby Kong, Calvin Huang, Jonathan Zhu, Colleen McHugh. Long non-coding RNA control of cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1533.